Himanshu Singh (IIT Guwahati, India)
LinkedIn: Himanshu Singh
Abstract: The four canonical DNA bases are subject to a wide range of chemical modifications that play critical roles in genome regulation. In recent years, numerous modified DNA bases and the enzymes responsible for their processing have been discovered, highlighting their importance in human diseases such as cancer and neurological disorders. Epigenetic DNA modifications enable cells with identical genomes to acquire distinct functional identities. While cytosine methylation is relatively well characterized, the biological roles of many other DNA modifications remain poorly understood, largely due to challenges in their site-specific detection.
Engineered DNA reader proteins that selectively recognize individual epigenetic marks offer a promising strategy for interrogating the genome at single-base resolution. Understanding the structural and dynamic principles governing DNA recognition by both natural and designed readers is essential for developing molecular probes to study chromatin biology and disease-associated defects in target recognition.
Using a combination of mutagenesis, NMR relaxation experiments, structural analyses, and MD simulations, we demonstrated that the selectivity of the first engineered reader for an oxidized CpG epigenetic mark depends on finely tuned conformational plasticity acquired during the directed evolution of its natural progenitor. Our findings reveal that specific dynamic features are critical for achieving both high affinity and selectivity in DNA recognition.
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